Methods and compositions for reducing or eliminating post-surgical adhesion formation

ABSTRACT

The present invention relates to a method for reducing adhesions associated with post-operative surgery. The present method comprises administering or affixing a polymeric composition preferably comprising chain extended, coupled or crosslinked polyester/poly(oxyalkylene) ABA triblocks or AB diblocks having favorable EO/LA ratios to a site in the body which has been subjected to trauma, e.g. by surgery, excision or inflammatory disease. In the present invention, the polymeric material provides a barrier to prevent or reduce the extent of adhesions forming.

This application is a division of pending application Ser. No.10/749,436 , filed on Dec. 31, 2003, which is a division of applicationSer. No. 09/688,625, filed on Oct. 16, 2000, now U.S. Pat. No.6,696,499, which is a division of application Ser. No. 08/890,802, filedon Jul. 11, 1997, now U.S. Pat. No. 6,136,333 which is acontinuation-in-part of application Ser. No. 08/678,762, filed on Jul.11, 1996, now U.S. Pat. No. 5,711,958.

The present invention relates to the discovery that the use ofbiodegradable polymeric compositions can prevent or reduce communicationbetween two sites after surgery and thereby significantly reduce and insome cases, actually prevent post-operative adhesions which often occurduring the initial phases of post-surgical repair.

BACKGROUND OF THE INVENTION

A major clinical problem relating to surgical repair or inflammatorydisease is adhesion which occurs during the initial phases of thehealing process after surgery or disease. Adhesion is a condition whichinvolves the formation of abnormal tissue linkages. These linkages whichform can impair bodily function, produce infertility, obstruct theintestines and other portions of the gastrointestinal tract (bowelobstruction) and produce general discomfort, e.g. pelvic pain. Thecondition can be life threatening. The most common form of adhesionoccurs after surgery as a result of trauma, although adhesion may occuras a result of other processes or events such as pelvic inflammatorydisease, mechanical injury, radiation treatment and the presence offoreign material.

Various attempts have been made to prevent postoperative adhesions. Forexample, the use of peritoneal lavage, heparinized solutions,procoagulants, modification of surgical techniques such as the use ofmicroscopic or laparoscopic surgical techniques, the elimination of talcfrom surgical gloves, the use of smaller sutures and the use of physicalbarriers (films, gels or solutions) aiming to minimize apposition ofserosal surfaces, have all been attempted. Unfortunately, very limitedsuccess has been seen with these methods. Barrier materials, in variousforms such as films and viscous intraperitoneal solutions, which aredesigned to limit tissue apposition, have also met with only limitedsuccess. The best of these barrier materials include cellulosicbarriers, polytetrafluoroethylene materials, and dextran solutions.Also, a number of films based on polylactic acid, polyglycolic acid andcopolymers of the two have proven to be unsuccessful. Indeed, mostbarrier materials have met with failure because these materials caninduce untoward biological effects, e.g., foreign body reaction.

U.S. Pat. No. 5,410,016 to Hubbell, et al. is directed tophotopolymerizable biodegradable gels for use as adhesion barriers, ascontrol release systems for drugs, to provide temporary protection oftissue surfaces and for adhering or sealing tissues together. Hubbell,et al. discloses water-soluble macromonomers containingphotopolymerizable groups on each end which are administered or placedon tissues prior to a photopolymerization step. After administration,the macromonomers are photopolymerized in situ in order to produce acrosslinked polymer on the tissue. The method of Hubbell, et al. suffersfrom the disadvantage that it is a cumbersome system, requiringadditional equipment and expertise which adds to the cost of thetreatment. In addition, the method suffers from the disadvantage thatthe patient must be irradiated with energy to polymerize themacromonomers during or after surgery, potentially compromisingsterility and complicating and prolonging the surgical process. Giventhe nature of the system used to polymerize macromonomers, the Hubbelsystem produces polymers of high crosslink density which are somewhatweak in structure. In contrast to the polymers of Hubbell, the presentinvention makes use of polymers which are polymerized prior to use inthe patient (“prepolymerized”).

Ideally, a physical barrier for adhesion prevention should be completelyabsorbable and nonreactive. In addition, it should stay in place in thebody with a minimum of suturing or stapling.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide polymeric barrierswhich may be used to substantially prevent tissue to tissue adhesionsand adhesions between tissue and implants and devices.

It is an additional object of the invention to provide polymericmaterials in film, other solid structures such as rods, cylinders,porous structures such as foams, dispersions, viscous solutions, liquidpolymers, sprays or gels which may be administered easily and withuniform results after surgery.

It is a further object of the invention to provide polymeric materialswhich may be used to substantially prevent adhesions and which may beeffective for delivering bioactive agents.

It is yet an additional object of the invention to provide bioabsorbablepolymeric materials which can be produced in a variety of formulationswhich have acceptable strength, are non-reactive with patient tissue andare bioabsorbable.

It is yet another object of the present invention to provide polymericbarriers which can be used in various forms, e.g., films, otherstructures such as rods and cylinders, foams, gels, dispersions, liquidpolymers, sprays or viscous solutions, to provide flexibility inadministration and use.

These and/or other objects of the invention may be readily gleaned fromthe detailed description of the present invention which follows.

SUMMARY OF THE INVENTION

The present invention relates to a method for eliminating or reducingpost-surgical tissue adhesions using polymeric materials which aresubstantially integral and relatively rapidly bioabsorbable. It is thecombination of these characteristics in polymers of the presentinvention which has produced favorable results in substantially reducingor even eliminating post-operative adhesions. Moreover, the method ofthe present invention is performed simply and in a cost-effective mannerwithout the need for additional or expensive equipment. Unlike the priorart methods, the present invention is used under sterile conditionswithout exceptional efforts to maintain sterility and avoids thenecessity of irradiating the patient In addition, certain polymers usedin the present invention (e.g. films or related preformed structures ofpolymer) exhibit sufficient strength and flexibility to be able toconform to a site to be protected and allow a suture to hold a polymerstructure in place at the site of surgery.

It now has been discovered that the polymers according to the presentinvention, which are able to generate an integral barrier, areadvantageously employed in reducing and even completely eliminatingpost-surgical adhesions. The present method comprises administering oraffixing to an area in a patient's body at risk for developingadhesions, a polymeric composition comprising AB diblocks (preferably,as di-diblocks, as discussed in greater detail herein) or ABA triblockswhich are chain-extended, coupled and/or crosslinked. Preferably, the Ablocks comprise aliphatic ester units, more preferably derived fromhydroxy acid units or their cyclic dimers and the like, even morepreferably a-hydroxy acid units. In many embodiments, the methodcomprises administering the instant polymer compositions to a sitewithin the patient's body which has been subjected to surgical repair orexcision. In the present invention, the polymeric material provides abarrier to prevent adhesions from forming. After this period ofprotection, the polymer will degrade and will be resorbed within thepatient's body and/or excreted from the patient's body. According to thepresent method, problems associated with non-absorbtion or foreign bodyreactions are significantly reduced or prevented.

The polymer may be administered in various forms such as films, otherstructures including rods, cylinders, foams, dispersions, viscoussolutions, liquid polymers, sprays or gels. The form a polymer takes atthe surgical site will depend upon the type of surgery which has beenperformed or the condition which is to be treated and the site to betreated. In addition, the need to deliver the polymer to a particularsite within the body may be determinitive of the form in which thepolymer is delivered. The present method may be used after virtually anysurgery to prevent tissue adhesion which occurs during the initialphases of post-surgical repair. Thus, in all applications where tissueis being repaired or excised, the polymers according to the presentinvention find utility to prevent adhesions. Generally, the polymers areused to prevent tissue to tissue adhesion and adhesions between tissuesand implants or devices, which occur after surgical procedures, as wellas other conditions, including certain disease states.

The present polymers preferably are based on polyester/poly(oxyalkylene)ABA triblocks or AB diblocks, where A is a polymer preferably comprisingaliphatic ester units, which are preferably derived from hydroxy acidunits or their cyclic dimers and the like, even more preferablyα-hydroxy acid units or their cyclic dimers and the like, such as arelated ester or lactone. Preferably the A block comprises α-hydroxyacidunits derived from an aliphatic α-hydroxy carboxylic acid or a relatedacid, ester or similar compound such as, for example, lactic acid,lactide, glycolic acid, glycolide, or a related aliphatichydroxycarboxylic acid or ester (lactone) such as, for example,β-propiolactone, ε-caprolactone, δ-glutarolactone, δ-valerolactone,β-butyrolactone, pivalolactone, α,α-diethylpropiolactone, ethylenecarbonate, trimnethylene carbonate, γ-butyrolactone, p-dioxanone,1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione,3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters of α-hydroxybutyricacid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproicacid, α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof The use of α-hydroxyacids in the present invention ispreferred. The A block of the triblocks and diblocks used in the presentinvention preferably comprises a poly(α-hydroxy-carboxylic acid), forexample, poly(glycolic acid), poly(L-lactic acid) and poly(D,L-lacticacid), because these polymers will degrade and produce monomeric unitswhich may be metabolized by the patient. The B block in the triblocksused in the present invention is preferably a hydroxyl, carboxylic acidor amine terminated poly(oxyalkylene) block (preferably, hydroxylterminated) and is more preferably either a poly(ethylene oxide)homopolymer or poly(ethylene oxide)-co-poly(propylene oxide) blockcopolymer.

The above triblocks or diblocks are preferably end-capped with hydroxylgroups and are chain-extended using difunctional chain extenders such asdiisocyanates, dicarboxylates, diesters or diacyl halide groups in orderto chain extend the triblocks into high molecular weight polymer chains.Alternatively, the triblocks may be end-capped with groups such ascarboxylic acid moieties or ester groups (which may be reacted directlyas ester groups, activated as “active” ester groups or converted toactive acyl groups such as acyl halides) or isocyanate groups and thenreacted with difunctional chain extenders such as diols, diamines,hydroxylamines, or polyoxyethylene (polyethylene glycol) orpoly(ethylene oxide)-co-poly(propylene oxide) block copolymer chainextenders (especially, in the case of water soluble or water dispersiblegels, dispersions or viscous solutions) among others, to produce chainextended polymers preferably having high molecular weight. It is thefact that the polymers according to the present invention preferablycomprise chain-extended trimers, which have relatively high molecularweights, or dimers, which cover a range of molecular weights, providepolymeric characteristics which are advantageously employed in barriersof various forms including a preformed structure such as a film, rod,tube, bead, foam or ring or dispersions, sprays, gels, liquid polymers,viscous liquids and viscous solutions, among others, according to thepresent invention.

In certain aspects of the present invention, preferred polymers for usein the present invention have the following characteristics: they areprepolymerized, chain-extended, substantially non-crosslinked andbiodegradable. In other instances, the polymers may be crosslinked.Preferred polymers are also non-reactive, i.e., they do not produce anunintended or adverse tissue reaction. The present polymers areadvantageously used as barrier materials to reduce or prevent adhesion.Polymers used in various preformed structures such as films according tothe present invention are sufficiently flexible to enable the polymer tosubstantially conform to the surface of the tissue to be treated, yet atthe same time have sufficient strength to function as an integral andtherefore, effective barrier to allow suturing the material to tissue.Polymers used in other forms such as gels, dispersions and viscoussolutions according to the present invention also have sufficientstructural integrity to be delivered to a site within the body andprevent adhesions at the same time that the polymers are water solubleand/or water dispersible in order to be delivered.

In the present invention, PELA is the generic name used to denote thepreferred polymers comprising poly(ethylene oxide) and poly(lactic acid)blocks, being chain extended with a diisocyanate, most preferablyhexamethylene diisocyanate. PELA polymers are generally designated withrespect to their composition by the average molecular weight of thepoly(ethylene oxide) chain and by their (EO/LA) ratio, where EO is thenumber of ethylene oxide units present and LA is the total number oflactoyl units (ester units) present. A general definition of EO/LA ratiois presented hereinbelow.

In the present invention, the ABA triblock is preferably a substantiallynon-water soluble unit comprising poly(hydroxy acid) blocks andpoly(oxyalkylene blocks), preferably poly(α-hydroxy acid) blocks andethylene glycol, diethylene glycol and poly(ethylene oxide) chains orpoly(ethylene oxide)-co-poly(propylene oxide) block copolymers. The Ablock of the ABA triblocks of the present polymers is biodegradable andranges in size from one monomeric unit (a monomeric unit within the Ablock being considered lactic acid, glycolic acid or a related hydroxyacid (ester) unit even where lactide and/or glycolide or relatedreactants containing more than one hydroxyacid unit are used to producethe A block) up to about 400 or more monomeric units, with a preferredsize ranging from about 4 to about 50 units, more preferably about 6 toabout 30 units, even more preferably about 8 to about 16 monomericunits, which length depends upon the length or molecular weight of the Bblock combined with the A block in triblocks according to the presentinvention. It is to be noted that the size of the A block may well falloutside of the above range, depending upon the overall physicalcharacteristics of the ABA triblock formed and the size of the B block.

The A block is derived preferably from an α-hydroxy acid as describedabove, more preferably from units of glycolic acid, lactic acid(preferably L or D,L mixtures to promote bioabsorbability) or mixturesthereof, in the form of glycolide or lactide reactants (as explained ingreater detail hereinbelow). In the final polymers to be used to reduceor prevent post-operative adhesion, the A blocks tend to create harddomains in the matrix and generally provide strength and structuralintegrity to the polymer. The A block is non-water soluble and is sizedin combination with the more water soluble/water dispersible B block inorder to preferably promote phase separation between the the A and Bblocks in the ABA triblock and the final polymer to be used to preventor reduce adhesions. Thus, the A block instills the final polymer withessential structural characteristics, which, in combination with the Bblock, results in a polymer which has excellent anti-adhesioncharacteristics (believed to be instilled by the B block) in combinationwith strength, structural integrity and biodegradability instilled bythe A block. In addition, in certain embodiments according to thepresent invention, the length of the A block is believed to be importantfor providing a material with a phase separated microstructure.

The B block preferably comprises poly(ethylene oxide) or poly(ethyleneoxide)-co-poly(propylene oxide) block copolymers and other PEO-richchains which fall in the molecular weight (M_(w)) range as definedhereinbelow. The B block may preferably vary in size from about 100 Da(dalton units) up to about 200,000 Da or higher, with a more preferredrange of about 400 Da up to about 20,000 Da. Even more preferably, the Bblock is a poly(ethylene oxide) ranging in size from about 400 to about10,000 Da. Based upon the teachings of the present invention, one ofordinary skill will now know to vary the length of the B block and the Ablock to provide polymers having excellent anti-adhesion properties,depending upon the type of final formulation desired and its deliverycharacteristics.

The ABA triblocks or AB diblocks according to the present invention aregenerally described according to the length (number of monomericrepeating units) of the B block [preferably, poly(ethylene oxide), therepeating unit being in this case ethylene oxide units] divided by thetotal number of monomeric units in both A blocks (preferably, anα-hydroxy acid such as lactic acid) of the ABA triblock or the A blockof the AB diblock. This ratio is referred to as the EO/LA ratio.Polymers comprised of ABA triblocks or AB diblocks which are chainextended, coupled or crosslinked pursuant to the present invention alsomay be described in terms of an EO/LA ratio for the polymer, in whichcase the EO/LA ratio simply represents the ratio of oxyalkylene units tomonomeric units in the entire polymer. The EO/LA ratio of the entirepolymer may be determined by NMR analysis. These polymers may also bedesignated with respect to their composition by the average molecularweight of the poly(ethylene oxide) (PEG) chain or chains and by theweight percentage of the PEG chain or chains in the triblock, diblock ortotal polymer. It should be noted, however, that in instances where thechain extender, coupler or crosslinking agent comprises a poly(ethyleneoxide) chain, the EO/LA ratio for the polymer may vary considerably fromthe EO/LA ratio found in the ABA triblock or AB diblock (the totalamount of EO may become considerably larger because of contribution ofEO from the chain extender, and consequently, the EO/LA ratio for thepolymer may be considerably larger than it is for the ABA triblock or ABdiblock). Likewise, the weight percentage of PEG found in such a polymermay also be quite different from that found in the ABA triblock or ABdiblock.

Without being limited by way of presentation, the concept of the EO/LAratio may be exemplified by a polymer described as a poly(ethyleneoxide)-lactic acid block copolymer (PELA) 6,000/3.8, which is ahexamethylene diisocyanate chain extended ABA triblock copolymercomprising PEG chains having an average molecular weight of 6,000 and anEO/LA ratio of 3.8. The triblock in this polymer comprises, therefore, a6,000 molecular weight PEG segment for the B block containingapproximately 136 ethylene oxide units and two A blocks each containing,on average, approximately 18 LA units. Alternatively, the same polymercan be designated as 6,000/69.8%, where 6,000 is the average molecularweight of the PEG chains, and 69.8% is the weight percentage of PEG inthe ABA triblock. For this PELA 6,000/3.8 polymer, the molecular weightof the triblock is approximately 8592 (6,000 for the PEG chain and twopoly (lactic acid) A blocks each having a molecular weight ofapproximately 1296, for a total for the two A blocks of 2592). Theweight percentage of the PEG block in this triblock is, accordingly,69.8% (6,000/8592).

Alternatively, by way of example, the ABA triblock described above maybe chain extended with, for example, the following chain extender:HDI-PEG4000-HDI, which is formed by reacting a poly(ethylene oxide)chain of molecular weight 4000 with two moles of hexamethylenediisocyanate. The repeating unit, after reaction of this chain extenderwith the ABA triblock described in the paragraph above is[(LA)₁₈-PEG6000-(LA)₁₈ -HDI-PEG4000HDI-]. The molecular weight of thetriblock 8592 (6000+2×18×72=2592) and that of the macrodiisocyanatechain extender is 2×168 (for the two HDI molceules)+4000 for the PEGchain. The MW of the repeating unit is therefore, 8592+4336=12928. Theweight % of PEG in the repeating unit is 77.4% (6000+4000=10,000;10,000/12928). In terms of the EO/LA ratio of the repeating unit, wehave a total PEG MW of 10000, which comprises 10000/44 EO units=227.3 EOunits. These units, divided by the 36 LA units present gives us a ratioof 6.3. Because it is difficult to define an average PEG MW in certaininstances, since we could get, for the example above, an average NW ofapproximately 6000, which could be the result of PEG 10000 in thetriblocks and 2000 in the chain extenders, or the result of simplyhaving PEG chains of 6000 in each of the triblock and chain extender.The exemplary polymer we describe above is a PELA 6000/4000/77.4%.

The preferred EO/LA ratio for polymers according to the presentinvention ranges from about 0.1 to about 100 or more, preferably about0.5 to about 30, more preferably from about 0.5 to about 10.0, morepreferably about 1.0 to about 5.0, more preferably about 1.5 to about4.5, even more preferably about 2.5 to about 3.5 and most preferablyabout 3.0. In certain instances, the EO/LA ratio may fall outside ofthese ranges, depending upon the final characteristics of the polymerswhich are desired. Preferred EO/LA ratios for individual polymers mayalso vary according to the size of the B block and the type ofchain-extender which is used. In certain embodiments, as the size(molecular weight) of the B block in the triblocks increases, thepreferred EO/LA ratio will tend to be somewhat less than in triblocksand polymers where the size of the B block is less.

Tailoring the properties of the antiadhesion barriers generated by thepresent polymers is based upon combining (a) the enhanced antiadhesionproperties attributed, by way of theory, by the PEG (B block) segments;(b) the biodegradability of the polyester, preferably poly(hydroxy acid)A blocks; and (c) the mechanical properties derived from the partiallyphase separated microstructure of the polymeric matrix.

The PEG (B block) content is related to the efficaciousness of thepolymer as an antiadhesion barrier. Higher PEG content may give rise togreater antiadhesion activity, but with fast polymer degradation. Sincethere is a requirement for the barrier to stay in place separating therelevant tissues for a determined period of time, there is an optimalEO/LA ratio which combines maximum PEG content with the biologicallyrequired residence time. In agreement with these basic considerations,preliminary animal data indicate that polymers of the present inventioncomprising PEG chains of a 6,000 molecular weight and having an EO/LAratio of approximately 3.0, display optimal properties as antiadhesionbarriers.

Based upon the teachings of the present invention, one of ordinary skillin the art will now know to vary the length of the A block to the Bblock in a manner which provides polymers having excellent structuralintegrity, biodegradability and activity which substantially inhibitspost-operative adhesion.

The polymers according to the present invention are prepolymerized,chain-extended and attain high molecular weight. The polymers may benon-crosslinked or crosslinked. In order to increase the molecularweight of the polymer produced, the end-capped ABA triblock or ABdiblock (which may be end-capped with hydroxyl, amine or carboxylic acidgroups) is chain-extended using difunctional compounds such asdiisocyanate, dicarboxylic acid compounds or derivatives of dicarboxylicacids such as diacyl halides. The product which is formed from thereaction of the chain extender or crosslinking agent with the ABAtriblock or AB diblock according to the present invention will dependupon the chemical nature of the nucleophilic (or electrophilic) moietieson the ABA triblock or AB diblock (or related multi diblocks) and theelectrophilic (or nucleophilic) moieties on the chain extender orcrosslinking agent. The reaction products can vary widely to producedifferent moieties, such as urethane groups, ester groups, urea groupsand amide groups, among numerous others. For example, in the case of anABA triblock (hydroxyl terminated) reacting with diisocyanate chainextenders, the product is a urethane chain extended polymer. In the caseof amine groups terminating the ABA triblocks reacted with diisocyanatechain extenders, the product is a urea. In the case of carboxylic acidgroups terminating the ABA triblocks (which can be converted toanhydrides or acyl halides) reacting with an amine terminated chainextender or crosslinking agent, the product is an amide. Preferably, thenucleophilic end-capped triblocks are chain-extended with diisocyanatecompounds in order to produce chain-extended polymers according to thepresent invention, although the chemical approaches, as explained above,may vary greatly. In the case of structures such as films, the chainextenders are used to provide greater molecular weight to the triblocks,thus enhancing structural integrity. In the case of gels, liquidpolymers and/or viscous solutions, the chain extenders or crosslinkingagents provide not only high molecular weight, viscosity control andstructural integrity, but also a degree of watersolubility/dispersibility consistent with the solubility and/ordispersibility of these polymers in water and the delivery of thesepolymers to a site within the patient's body. Thus, the chain extendersmay be used to provide a number of benefits without using the approachof shortening the A blocks, which may hamper the beneficialmorphological and mechanical effect.

The final polymers according to the present invention may be non-watersoluble or in certain liquid, viscous solution and/or gel applicationsmay absorb significant quantities of water. Certain polymers accordingto the present invention are water soluble, especially where the polymerhas a high EO/LA ratio.

The polymers according to the present invention may be crosslinked inaddition to. being chain-extended. Crosslinking agents may be similar tothe chain extenders used in the present invention, with the exceptionthat the crosslinking agents contain at least three reactive functionalgroups, in contrast with chain extenders, which generally contain onlytwo reactive functional groups.

The present invention therefore relates to polymer compositions and tomethods of substantially reducing or preventing tissue adhesions inpatients comprising exposing damaged tissue in a patient to a polymericcomposition of the present invention in various forms, such as films,viscous solutions or gel forms, among numerous others. Depending uponthe type of tissue to be treated, the extent of injury which hasoccurred, the nature of the surgical procedure performed and the way thepolymer is administered, the polymeric composition according to thepresent invention may be used advantageously in different forms such asan integral film, a dispersion as well as a gel or a viscous solution.The present polymers may be used in conjunction with any type ofsurgical procedure, and in particular, intraabdominal, intraperitonealor in pelvic surgery. More specifically, the present polymers may beused to substantially reduce or prevent adhesions in conjunction withmusculoskeletal surgery, abdominal surgery, gynecological surgery,ophthalmic, orthopedic, central nervous system, cardiovascular andintrauterine repair.

DETAILED OF THE INVENTION

The following terms shall be used throughout the specification todescribe the present invention.

The term “adhesion” is used to describe abnormal attachments betweentissues or organs or between tissues and implants (prosthetic devices)which form after an inflammatory stimulus, most commonly surgery, and inmost instances produce considerable pain and discomfort. When adhesionsaffect normal tissue function, they are considered a complication ofsurgery. These tissue linkages often occur between two surfaces oftissue during the initial phases of post-operative repair or part of thehealing process. Adhesions are fibrous structures that connect tissuesor organs which are not normally joined. Common post-operative adhesionsto which the present invention is directed include, for example,intraperitoneal or intraabdominal adhesions and pelvic adhesions. Theterm adhesion is also used with reference to all types of surgeryincluding, for example, musculoskeletal surgery, abdominal surgery,gynecological surgery, ophthalmic, orthopedic, central nervous system,cardiovascular and intrauterine repair. Adhesions may produce bowelobstruction or intestinal loops following abdominal surgery, infertilityfollowing gynecological surgery as a result of adhesions forming betweenpelvic structures, restricted limb motion (tendon adhesions) followingmusculoskeletal surgery, cardiovascular complications includingimpairing the normal movement of the heart following cardiac surgery, anincrease in intracranial bleeding, infection and cerebrospinal fluidleakage and pain following many surgeries, especially including spinalsurgery which produces low back pain, leg pain and sphincterdisturbance.

The term “polymer” is used to describe compositions according to thepresent invention which are used to reduce and/or prevent adhesions.Polymers according to the present invention may range in molecularweight (average molecular weight) from about 1,000-3,000 to severalmillion or more and as described, include oligomers of relatively lowmolecular weight.

The terms “poly(ethlyene glycol)”, “poly(oxyethylene)” and poly(ethyleneoxide) are used interchangably to describe the present invention. Thesepolymers, of varying weights, are used in the B block of ABA triblocksand AB diblocks according to the present invention as well as in chainextenders and crosslinking agents which may also be used in the presentinvention. The terms “poly(oxyalkylene) containing” and “poly(ethyleneoxide) containing” and are used to describe certain polymeric chainswhich contain at least some amount of poly(oxyalkylene) or poly(ethyleneoxide). The terms “poly(oxyalkylene) rich” and “poly(ethylene oxide)rich” are used to describe certain polymeric chains containing at least50% by weight (of the total weight of the polymeric chain described)poly(oxyalkylene) or poly(ethylene oxide).

The term “polyester” is used to describe polyester A blocks of ABAtriblocks and AB diblocks used in polymeric compositions according tothe present invention where A is a polymeric polyester unit which may bederived from an aliphatic hydroxy carboxylic acid or a related ester,lactone, dimeric ester, carbonate, anhydride, dioxanone or relatedmonomer and is preferably derived from an aliphatic α-hydroxy carboxylicacid or related ester, such units derived from the following: including,for example, lactic acid, lactide, glycolic acid, glycolide, or arelated aliphatic hydroxycarboxylic acid, ester (lactone), dimeric acidor related compound such as, for example, β-propiolactone,ε-caprolactone, δ-glutarolactone, δ-valerolactone, β-butyrolactone,pivalolactone, α,α-diethylpropiolactone, ethylene carbonate,trimethylene carbonate, γ-butyrolactone, p-dioxanone,1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione,3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters of α-hydroxybutyricacid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproicacid, α-hydroxy-o-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof The use of α-hydroxyacids and their correspondingcylic dimeric esters, especially lactide and glycolide in the presentinvention, is preferred. It is noted that in using certain of thedescribed monomers according to the present invention, the monomericunits which are produced are not specifically ester groups, but mayinclude such groups as carbonate groups, urethane groups and relatedgroups which are derived from the above-described monomers. It will beunderstood that the term polyester shall encompass polymers which arederived from all of the above monomers, with those which actuallyproduce ester units being preferred.

The terms “poly(hydroxy carboxylic acid)” or “poly(α-hydroxy carboxylicacid)” are used to describe polyester A blocks of ABA triblocks or ABdiblocks used in polymeric compositions according to the presentinvention where A is a polymeric polyester unit derived from analiphatic hydroxy carboxylic acid or a related ester or dimeric esterand is preferably derived from an aliphatic α-hydroxy carboxylic acid orrelated ester, including a cyclic dimeric ester, such as, for example,lactic acid, lactide, glycolic acid, glycolide, or a related aliphatichydroxycarboxylic acid or ester (lactone) such as, for example,ε-caprolactone, δ-glutarolactone, δ-valerolactone, γ-butyrolactone andmixtures, thereof, among numerous others as set forth herein. The use ofα-hydroxyacids and their corresponding cylic dimeric esters, especiallylactide and glycolide in the present invention, is preferred.

The term “triblock” is used to describe polymeric units which are usedin certain embodiments to produce the polymers according to the presentinvention which comprise a first polyester A block covalently linked toa poly(oxyalkylene) B block as described above which is, in turn,covalently linked to a second polyester A block. Triblocks according tothe present invention may be terminated by hydroxyl, amine, or carboxylmoieties, but in preferred embodiments, are terminated with hydroxylgroups which can be readily covalently linked to chain extenders,crosslinking agents or other groups which contain electrophilicmoieties, to produce the final polymers which are used in the presentinvention.

The term “diblock” is used to describe polymeric units which comprise afirst polyester A block [preferably, a poly(hydroxy carboxylic acid)polyester] covalently linked to a poly(oxyalkylene) B block as describedabove. In the present invention, diblocks may be formed, for example, byinitiating a polymerization of hydroxy carboxylic acid (or equivalentmonomeric, dimeric or related building blocks) with a hydroxyl, amine orcarboxyl-terminated poly(oxyalkyelene) block which is end-capped (on oneend of the polymer) with a non-reactive group (for example, an alkyl,aryl or aralkyl group or substituted alkyl, aryl or aralkyl group,preferably, a C₁-C₁₂ alkyl group or an equivalent, or a protecting groupwhich can be removed to provide a free nucleophilic moiety at a latertime). The diblocks which are produced may then be further reacted withchain-extenders, crosslinking agents and the like to produce polymersaccording to the present invention having favorable EO/LA ratios for usein reducing and/or preventing adhesion. Diblocks may be used in much thesame way that ABA triblocks are used in the present invention, i.e., asbuilding polymeric units of the polymers according to the presentinvention.

The term “multi-diblock” is used to describe compounds which containunits of diblocks which have been linked through chain extenders orcouplers, in the case of diblocks, or crosslinking agents into astar-like or comb-like configuration.

The term “tion-water soluble” or “substantially non-water soluble” isused to describe certain preferred ABA triblocks or AB diblocks used invarious forms according to the present invention. In the presentinvention, in forms such as viscous solutions, gels or emulsions inwhich the polymers are substantially water soluble, the ABA triblocks orAB diblocks may be water soluble or non-water soluble. AB diblocks ormultiblocks according to the present invention may be non-water solubleor water soluble. Non-water soluble triblocks or diblocks according tothe present invention are soluble in water up to a limit of no more thanabout 0.5-0.6 g per 100 ml of water, preferably less than about 0.2 gper 100 ml of water. In determining water solubility, triblocks ordiblocks according to the present invention are dissolved in, agitatedor mixed in water at room temperature (i.e., at a temperature of about20-23° C.) for a period of two hours. It is noted that in the presentinvention, chain-extended triblocks which are used to produce structuressuch as films according to the present invention are also preferablysubstantially non-water soluble, i.e, they are limited in watersolubility to no more than about 0.2 mg/ml. This limitation of watersolubility reflects the fact that in certain embodiments according tothe present invention, substantially non-soluble triblocks or diblockswhich are preferably used in the present invention comprise at leastabout 25-30% by weight of A blocks.

An amount of the A blocks in the ABA triblocks or AB diblocks comprisingat least about 25-30% by weight generally renders the triblocks ordiblocks according to the present invention substantially non-watersoluble. It is to be noted that water solubility or the absence of watersolubility of the triblocks or diblocks may depend upon the molecularweight of the material. This characteristic is advantageous in thepresent polymeric compositions because the length and/or size of the Ablock instills structural integrity and biodegradability to the finalpolymer, but also, by virtue of the relative hydrophobicity~of theblock, tends to reduce the water solubility of the ABA triblock or ABdiblock. Consequently, polymeric compositions according to the presentinvention which contain a proper balance of A block or blocks to B blockhave a slow rate of biodegradability and consequently, a longer periodof interaction with tissue to be protected from adhesion formation. Thisis reflected overall in the EO/LA ratio of the polymers according to thepresent invention.

Polymers to be used in viscous solutions, dispersions and/or gelsaccording to the present invention are preferably water soluble and/orwater dispersible and may use many of the same or similar ABA triblocksor AB diblocks used in polymeric structures such as films according tothe present invention. In certain applications of the presentinventions, in particular, in producing a liquid version which issubstantially non-water soluble, having acceptable viscosity and flowcharacteristics for favorable administration, the polymers are actuallysubstantially non-water soluble. Consequently, in applications such asfilms as well as in certain embodiments of the gel, dispersion andviscous solution applications, regardless of the way the polymers areadministered, the ABA triblocks or AB diblocks which are preferably usedare substantially non-water soluble. In certain alternative embodimentsof the gels, dispersions and viscous solutions of the present invention,especially where the polymers are to be readily water dispersible, watersolubility of the ABA triblocks or AB diblocks may be an advantageouscharacteristic, in which case, the inclusion of A blocks which compriseas little as about 1-5% by weight of the ABA triblocks or AB diblocksmay be useful in the present invention.

The term “EO/LA ratio” is used to describe the relative amount ofpoly(ethylene oxide) or poly(ethylene oxide)-co-poly(propylene oxide)and ester units (such term including monomeric units which are nottechnically ester units, as described in greater detail herein butpreferably, are hydroxy carboxylic acid units, even more preferably,α-hydroxy carboxylic acid units and most preferably, lactic acid units)which are used in ABA triblock or AB diblock copolymers andchain-extended polymers according to the present invention. This termrefers to the length (number of monomeric units) of the B block[preferably, poly(ethylene oxide), the monomeric units being ethyleneoxide units] divided by the total number of hydroxy acid (ester) unitsin both A blocks (preferably, lactic acid) of the ABA triblock or in theA block of the AB diblock as described hereinabove. Polymers comprisedof ABA triblocks or AB diblocks which are chain extended pursuant to thepresent invention are also described in terms of an EO/LA ratio. TheEO/LA ratio for polymers according to the present invention generallyranges from about 0.1 to about 100 or more, preferably ranges from about0.5 to about 30 or more, more preferably from about 0.5 to about 10.0,more preferably about 1.0 to about 5.0, more preferably about 1.5 toabout 4.5, even more preferably about 2.5 to about 3.5 and mostpreferably about 3.0. In certain instances, the EO/LA ratio may falloutside of these ranges, depending upon the final characteristics of thepolymers which are desired. In the case of polymeric films, the EO/LAratio preferably ranges from about 0.1 to about 25 or more, morepreferably about 0.5 to about 10, even more preferably about 1.0 to 5.0,even more preferably about 1.5 to about 4.5 and even more preferablyabout 2.5 to 3.5, with about 3.0 within this range being particularlypreferred. In the case of viscous solutions, dispersions and/or gels,the polymers may contain EO/LA ratios which range up to 30 or more. Itis noted that in the case where a hydrophobic unit is used in the Bblock (for example a propylene oxide unit or higher alkylene oxide unit,this unit is considered as being a component in the denominator (LA) ofthe EO/LA ratio.

The term “prepolymerized” is used to describe the polymers according tothe present invention which have been completely reacted before beingintroduced or administered to a patient to be treated. Prepolymerizedpolymers according to the present invention stand in contrast topolymers which may be polymerized in situ, i.e., at the site ofadministration in the patient. Prepolymerized polymers of the presentinvention are utilized to create both preformed structures, e.g.,compositions having three-dimensional structure such as films,cylinders, spheres, rods, blocks, tubes, beads, foam or rings, etc. andrelated structures, and non-preformed compositions such as sprays, gels,liquid polymers, viscous solutions and dispersions, among others.

The term “crosslinked” or “crosslinker” is used to describe agents whichcovalently bond the ABA triblocks or AB diblocks to other triblocks,diblocks or other moieties in the present polymers. As used herein, acrosslinker refers to a chemical compound which contains at least three(3) reactive moieties, for example, nucleophilic and/or electrophilicmoieties, or moieties such as double-bonds, which can react through aradical initiated mechanism. In preferred embodiments, crosslinkingagents according to the present invention have at least three of thesame type of moieties, for example nucleophilic, electrophilic orradical-initiated moieties in order to facilitate the reaction of thecrosslinker with triblocks and diblocks according to the presentinvention. In many respects, crosslinking agents are related tochain-extending agents in the present invention except thatchain-extending agents contain only two reactive moieties, whereascrosslinking agents contain at least three reactive moieties. Exemplarycrosslinking agents which can be used in the present invention includethose which contain at least three isocyanate moieties, for example,isocyanurate, among numerous others, or a mixture of reactive moieties,such as carboxylic acid and hydroxylic groups (an example being citricacid or tartaric acid, among numerous others) and amine groups. One ofordinary skill in the art will be able to readily determine the type andamount of crosslinking agent which may be used in the present inventionin order to facilitate the therapeutic method according to the presentinvention and the delivery of the polymers to a treatment site in apatient.

In the present invention reaction of an AB diblock with a crosslinkingagent may produce a star molecule or, in other instances, differentstructures such as a comb polymer, for example, but not a crosslinkedsystem per se. Inasmuch as the AB diblock will generally contain onlyone reactive moiety per molecule (except in the case where one of thetwo blocks contains a blocking group which may be removed and thenreacted subsequent to the initial formation of the AB diblock), the useof crosslinkers will produce predetermined structures such as star orcomb molecules. The inclusion or incorporation of an additional moietyin the diblock to which a crosslinking agent can react will generate amore elaborate crosslinked system akin to that produced with the ABAtriblocks of the present invention.

The term “non-crosslinked”, “substantially non-crosslinked”,“crosslinked” or “substantially crosslinked” are used to describe thepolymers according to the present invention which exhibit or display asubstantial absence of crosslinking or, in other embodiments,substantial crosslinking. Polymers according to the present inventionare advantageously associated with substantial post-surgical adhesionprevention or reduction. In certain embodiments, the present polymersactually prevent adhesions. Polymers according to the present inventionwhich are considered substantially non-crosslinked preferably containless than about 1.0% crosslinking, more preferably less than about 0.5%by weight crosslinking, even more preferably less than about 0.1% byweight crosslinking, most preferably less than about 0.05% by weightcrosslinking are advantageously employed in the present invention. Asused herein, reference to 1.0%, 0.5%, 0.1% etc. crosslinking refers tothe amount by weight of a crosslinker which may be found in the polymersof the present invention. In other embodiments, polymers may becrosslinked, i.e., they may contain substantially more crosslinkingagent than 1.0% by weight crosslinking agent.

The polymeric compositions according to the present invention arepreferably chain-extended rather than crosslinked, but may becrosslinked in addition to being chain extended. It is also possible toproduce crosslinked, non-chain extended polymers according to thepresent invention, but these polymers are generally crosslinked withmore hydrophilic chain extenders in order to maintain a favorable EO/LAratio. In certain preferred embodiments, the polymers are both chainextended and crosslinked. In the present compositions, chain extensionprovides the type of structural integrity and uniformity associated withthe exceptional performance of the polymers of the present invention asanti-adhesion barriers. While not being limited by way of theory, it isbelieved that chain extension alone or in combination with crosslinking,in contrast to mere crosslinking with hydrophobic chain extenderswithout chain extension, allows a degree of mobility and flexibility ofthe hydrophilic B block which is consistent with anti-adhesion activity.

The polymeric compositions according to the present invention provide anenvironment in which the A blocks (of the ABA triblock or AB diblock)will form hydrophobic, and often partially crystalline, hard microphasesof high structural integrity and the B blocks will form hydrophilic,flexible phases, which are believed to be primarily responsible for goodanti-adhesion activity. The formation of this microstructure, which isbelieved to be associated with polymeric compositions according to thisinvention and in particular, the flexibility of the PEG B blocks,produces excellent barriers for the reduction or prevention ofpost-surgical adhesions. Hydrophobic crosslinking of the triblocksaccording to the present invention without chain-extension (in contrastto hydrophilic crosslinking which may be used advantageously) not onlylimits molecular mobility, of special importance being its effect on thePEG segments, but also hampers or in certain instances, is believed toprevent microphase segregation from taking place. These two phenomenaare believed to be associated with the production of less successfulanti-adhesion barriers.

In general, crosslinking, especially if crosslinking density is high,prevents or at least substantially limits phase separation and to agreater extent, crystallization. In the present invention, thelimitation of phase separation and crystallization will depend on thecrosslinking density which is a function not only of the number oftrimers which are crosslinked to those which are chain extended, butalso on the molecular weight of the triblock and MW weight of itsdifferent components. In addition, the degree to which crosslinking willlimit phase separation (and also crystallization) will depend on themolecular weight and flexibility of the crosslinker. Clearly, theshorter the crosslinker, the greater the decrease in molecular mobilityand therefore, phase separation. The effect of the crosslinker beinghydrophobic or hydrophilic on phase separation and molecular orsegmental mobility is two-fold: a) hydration will render the crosslinkermore flexible and b) if the crosslinker is crystalline, itscrystallinity will be destroyed by hydration. One is therefore, notlimited to relatively low molecular weights of the crosslinker where,due to perturbations of the short chain, the polymer is unable tocrystallize.

As used in the present invention, the ABA triblocks or AB diblocks usedin the present polymers are preferably chain extended. The chainextenders which are used are difunctional compounds which react with theend-cap group of the triblocks to produce the chain extended triblocksaccording to the present invention. In the present invention, the amountof chain extender which is included within the polymers according to thepresent invention may vary. Thus, the molar ratio of chain extender toABA triblock in the present polymers varies from about 0.5 to about 2.0(about 1:2 to about 2:1, based upon the number of moles of difunctionalchain extender and the number of moles of ABA triblock, more preferablyabout 0.8 to about 1.2 and most preferably about 1.0. In the case ofdiblocks, the preferred molar ratio of chain extender to to AB diblockvaries from about 0.25 to about 1.0, with a more preferred ratio ofabout 0.5 to 1.0. When used with diblocks, the chain extenders are moreaccurately described as couplers, because they couple two diblockstogether to form a di-diblock. It is noted that in synthesizing thepresent chain-extended polymers, the amount of chain extender which isreacted with difunctional triblock or diblock to produce polymer isgenerally slightly higher than the amount which is expected to beincluded in the final synthesized polymers.

Chain extenders which are used in the present invention, preferablycontain no more than about 1% by weight of a crosslinking compound (suchterm signifying a compound containing at least 3 functional groups whichcan react with the end-cap group of the triblock and which generallyappear in a chain extender sample as a side product of the synthesis orproduction of the chain extender), more preferably, less than about 0.5%by weight of a trifunctional compound and even more preferably less than0.1% by weight. In certain embodiments, it is preferable to employ adifunctional chain extender which contains as little trifunctional (orhigher functionality ) compound as is practical. Also, the occurrence ofside reactions which would lead to crosslinking of the polymers isnegligible, due to both compositional as well as experimental parametersof the synthesis of the polymers of the present invention. Of course, incertain embodiments which separately employ crosslinking agents (eitheralone or in addition to chain extenders), the inclusion of weightpercentages of crosslinking agents outside of the above-described weightranges is within the scope of the present invention.

In the case of polymers which are used in structures such as films, thechain extenders are preferably non-water soluble. In the case ofpolymers which are used in systems such as water soluble gels,dispersions or viscous solutions, the chain-extenders are preferablyhighly water soluble. Preferred water soluble chain-extenders include,for example, polyethylene glycol diisocyanates or poly(ethyleneoxide)-co-poly(propylene oxide) copolymer diisocyanates, with thepolyethylene glycol or poly(ethylene oxide)-co-poly(propylene oxide)copolymer chain ranging in molecular weight from about 200 to about20,000 or more with a preferred molecular weight ranging from about 600to about 15,000, even more preferably about 600 to about 10,000. Incases where the preferred embodiment is a non-water soluble polymer in aliquid form, the chain extenders may also be substantially non-watersoluble. The role of the chain extenders in the sgels and/or viscoussolutions according to the present invention is to promote the watersolubility/dispersibility of the polymers and affect their viscosity inan effort to provide polymers which are readily deliverable to a site ina patient's body and also to fine tune the kinetics of degradation, thedilution and/or the solubilization of these polymers, to obtain optimalresidence time and enhance the performance of the polymer as a barrierbetween tissue planes.

In certain preferred embodiments according to the present invention, byutilizing chain extenders rather than crosslinking agents, the presentpolymers are substantially non-crosslinked, yet integral, and have theadvantage of having excellent structural integrity and characteristicssuch as strength and flexibility, which are advantageous for producingan efficient barrier for preventing adhesions. Also its is believed thatthe present polymers substantially avoid the formation of particles orbreak-down products which occur in many of the prior art polymercompositions.

As an advantageous feature of the present invention, the polymers of thepresent invention are employed in the present invention to substantiallyreduce or prevent adhesions. While not being limited by way of theory,it is believed that the polymers according to the present inventionwhich have a favorable EO/LA ratio allow greater mobility ofpolyoxyalkylene blocks (and in particular, polyethylene oxide blocks)within the ABA triblock or AB diblock used in the present invention, acondition which is believed to at least partially explain the favorableresults obtained by the present polymers in substantially reducing orpreventing adhesions. Chain extended polymers according to the presentinvention are more likely to enhance phase separation of the distinct Aand B blocks which comprise the triblocks, a condition which isassociated with the superior performance of the polymers of thisinvention as anti-adhesion barriers. It is preferred that the polymersof the present invention should be chain extended and substantiallynon-crosslinked, or chain extended and crosslinked while maintaining afavorable EO/LA ratio of the entire polymer as well as preservingflexibility and segmental mobility, as much as possible.

Polymers which are simply crosslinked (without chain extension) are alsouseful in the present invention, provided that the crosslinking agent issubstantially hydrophilic in composition and allows the retention of therequired degree of flexibility and segmental mobility.

The term “integral” is used to describe polymers according to thepresent invention which are substantially non-permeable to mesenchymalcells, platelets, blood cells and other cells which are involved in thebiology of adhesion formation. Integral polymers preclude cells whichare involved in the adhesion process from crossing the polymer barrierand initiating the adhesion process. Integral polymers also exhibitfavorable physical characteristics and mechanical properties consistentwith- substantially reducing or eliminating adhesions.

The term “chain extended” is used to describe polymers according to thepresent invention wherein the basic triblock or diblock is reacted witha difunctional chain extender to increase the molecular weight of thepresent polymers. In certain preferred embodiments, especially in theform of films, the present polymers are substantially non-crosslinkedand are instead, chain-extended to provide sufficiently high molecularweight polymer chains to enhance the strength and integrity of the finalpolymer film compositions as well as affecting the rate of degradation.It is noted that chain extension of the polymers provides adequatestrength and integrity of the final films and other structures, yetallows a degree of motility of the individual polyoxyalkylene B blockswithin the ABA triblock or AB diblock in order to maximize the adhesioninhibiting characteristics of the films. In contrast, hydrophobicallycrosslinked polymers which are not chain extended, provide a more rigidstructure which is believed to severely limit movement of the individualpolymeric blocks.

Preferred chain extenders for use in the present invention includediisocyanates of the general formula:

where R′ is a C₂ to C₁₂, preferably a C₂ to C₈ alkylene group, acycloalkyl or cycloalkyl-containing group, an aryl or aryl-containinggroup, 4,4′-diphenylmethane, toluene, naphthalene,4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene or p-phenylene. Equivalents ofdiisocyanates may also be used as chain extenders in the presentinvention. Additional chain extenders may include macrodiisocyanatesincluding isocyanate terminated poly(oxyalkylene) including isocyanateterminated polymers comprising poly(ethylene oxide) and polyethyleneoxide)-co-poly(propylene oxide), among others.

Additional preferred chain extenders for use in the present inventioninclude, for example, those according to the formula:

where R″ is a C₀ to C₁₂, preferably a C₂ to C_(8,) alkylene group or ahydroxyl or carboxylic acid substituted alkylene group, alkene, acycloalkyl, hydroxyl or carboxylic acid-containing cycloalkyl orcycloalkyl-containing group, an aryl or aryl-containing group or apolyoxyalkylene chain comprised of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide) or other poly(ethylene oxide) richchains and L is hydroxyl, a halide such as Cl, I or Br or an ester groupwhich can be prepared from a hydroxyl group such as an alkyl, phenyl,benzyl or substituted alkyl, phenyl or benzyl group, including activatedester groups such as a tosyl group, mesyl group or related activatinggroups.

The term “biodegradable” relates to the characteristic whereby a polymerwill degrade in the body. The polymers according to the presentinvention readily degrade in vivo and breakdown readily into monomericunits such as hydroxy acids. In the case of the PEG chains (B blocks),although these are not biodegradable, they are readily excreted by thepatient upon degradation of the A block. The degradation of the presentpolymers mainly takes place through the hydrolysis of reactive bonds inthe A block, such as aliphatic esters. The hydrolysis reaction isgenerally dependent upon pH. The rate constant for hydrolysis tends tobe much higher at high pH (greater than 9.0) and low pH (less than 3.0)than at neutral pH (6.0 to 8.0). The rate constant for hydrolysis tendsto be higher under basic conditions than under acidic conditions.

The A blocks of the triblocks and diblocks of the present polymers tendto be biodegradable, whereas the poly(oxyalkylene) B blocks of thetriblocks, diblocks and chain extenders tend not to be biodegradable. Inthe case of water-soluble chain extenders and crosslinking agents whichare preferably utilized in gels and viscous solutions according to thepresent invention, these chain extenders and crosslinking agents, whichgenerally are highly water soluble, tend not to be biodegradable. Inaddition, when using polymers containing A blocks derived from α-hydroxyacids, the polymeric A blocks will degrade to individual α-hydroxy acidswhich are biosynthetically useful and may be involved in the patient's“biochemistry”. In contrast, however, although the poly(oxyalkylene)polymeric B blocks are biocompatible, they are neither biodegradable norbioabsorbable. Thus, in using the polymers according to the presentinvention it is recognized that the poly(oxyalkylene) blocks will remainas polymeric units in vivo until such time as the blocks are excreted.Consequently, the choice of an upper molecular weight range of thepolyoxyalkylene block in the polymers according to the present inventionwill very much depend on the ability of the body to excrete or otherwiserid the body of the material.

The term “strength”, “mechanical strength” or “sufficient suture-holdingability” describes favorable mechanical and/or physical characteristicsof the present polymers and reflects the fact that preferred polymersfor use in the present invention (generally, as films) having amechanical strength which is sufficient to allow a suture to be used toanchor the polymer to a tissue site without appreciable tearing orripping of the film. These preferred polymers according to the presentinvention have an Ultimate Tensile Strength value preferably within therange of about 5-35 MPa and Elongation at Break values generally withinthe range of about 400-2000%.

The term “flexible” is used with respect to a physical description ofthe polymers of the present invention to reflect the fact that thepresent polymers are essentially non-rigid and non-brittle, andgenerally display an elastomeric behavior and tend to be conformable toa tissue surface to be treated. That is, the present polymers containsufficient flexibility and are pliable enough to substantially conformto the contours of the tissue surfaces to be treated. Thus, polymericcompositions according to the present invention have a Young's Moduluspreferably within the range of about 50-150 MPa.

The term “homogeneous” is used to describe preferred polymers accordingto the present invention. The term homogeneous is associated with theinclusion in the final polymer compositions of a population of triblocksand diblocks which are generally of the same size and preferably have apolydispersity of between about 1.0 and 2.0, more preferably about 1.1to about 1.5 and even more preferably about 1.1 to about 1.2.Homogeneous triblocks and diblocks are associated with reproduciblemechanical and physical characteristics and favorably consistentbiodegradability.

The term “structure” is used to describe polymers according to thepresent invention which have form, size and dimensions which areestablished outside the body and will not significantly change uponbeing placed inside the body of the patient to be treated. The termstructure embraces not only flat surfaced structures (i.e., films) inthe traditional manner, but also cylinders, tubes and other threedimensional structures which are not substantially changed by theanatomy of the patient into which the structure has been placed.

The term “gels” is used to describe dispersions or suspensions ofpolymer which have been formed by dissolving, suspending or dispersingpolymer in an aqueous solution for delivery to a site within thepatient's body in order to prevent adhesions. Gels of the presentinvention typically contain polymer in a sterile aqueous solution (suchsolution comprising saline solution, sterile water or a water/ethanolmixture) at a viscosity ranging from about 100 to about 150,000 or more,preferably about 500 centipoise units up to about 50,000 centipoiseunits or more. More preferably, the gels are delivered in sterile,isotonic saline solution at a viscosity ranging from about 2000centipoise units up to about 30,000 centipoise units depending upon theapplication. In certain aspects according to the present invention,liquid polymeric compositions comprising non-water soluble polymers mayalso be used.

Gels according to the present invention may be used in numerousapplications to reduce or prevent adhesions, but preferably are employedto reduce or prevent adhesions following general surgical procedures andrelated surgeries which are minimally invasive. Gels utilize non-watersoluble ABA triblocks which are chain extended with water-soluble orhydrophilic chain extenders in order to render the overall polymericcomposition water dispersible or water soluble.

Certain phases within the gel polymer compositions will beadvantageously non-water soluble in order to promote the structuralintegrity and reduce the overall rate of biodegradability of the gelformulations in the body.

The term “viscous solution or suspension” is used to describefree-flowing solutions or suspensions of polymers according to thepresent invention wherein the solution has a viscosity which is greaterthan about 1 centipoise unit and less than about 60,000 or morecentipoise units, more preferably about 1000 centipoise units to about40,000 centipoise units or more, even more preferably about 2,000centipoise units to about 20,000 centipoise units and above within thisrange. Viscous solutions or suspensions of polymers according to thepresent invention at viscosities approaching the high end of the rangeof viscosities may be indistinguishable from gels at the low end of aviscosity range. The present invention also contemplates liquidpolymeric compositions having appropriate viscosity and flowcharacteristics and their use to reduce and/or prevent adhesions.

In the present invention, the ABA triblock or AB diblock is a unit whichis generally comprised of ester units derived from a variety of monomersas described hereinabove and preferably comprises poly(hydroxy acid)polymers in the A block and poly(oxyalkyelene) polymers in the B block.The A block is however, substantially biodegradable and ranges in sizefrom one monomeric unit up to about 400 or more monomeric units, with apreferred size ranging from about 4 to about 50 units, more preferablyabout 6 to about 30 units, even more preferably about 8 to 16 units. TheA block preferably is derived from an alpha-hydroxy acid or a relatedester or lactone which produces monomer units of alpha-hydroxy acidwithin the polymeric chain as will be described in greater detail below.More preferably the A block is derived from units of glycolic acid,lactic acid or mixtures thereof, in the form of glycolide or lactidereactants (dimeric α-hydroxy acids as explained in greater detailhereinbelow). The B block preferably comprises poly(ethylene oxide) orpoly(ethylene oxide)-co-poly(propyleneoxide) block copolymers. Incertain aspects of the present invention, for example, where a polymercomprises a sufficient weight percent of poly(ethylene oxide) units inchain extenders and/or crosslinking agents to instill the overallpolymer with a favorable EO/LA ratio, the B block may be hydrophobic orhydrophilic and derived from, for example, diols, diamines anddicarboxylic acids, among other equivalent compounds.

Examples of such diol, diamine and diacarboxylic acid compounds include,for example, OH-terminated diol molecules such as ethylene glycol,butanediol, OH-terminated polycaprolactone chains ranging in molecularweight from several hundred up to several thousand or more (4,000+),poly(propylene glycol) also ranging in molecular weight from severalhundred to several thousand or more (4000+), OH-terminated polyesters oroligoesters such as OH-terminated poly(ethylene succinate) orpoly(hexamethyleneadipate) or polyfunctional diols such as tartaric acid(containing two OH groups which are reactive with isocyanates and twocarboxylic acid groups, which, in carboxylate form, will function toenhance the overall hydrophilicity of the composition and can serve toprovide a material with pH dependent water solubility). Additionalexamples of such compounds include amine-containing compounds(preferably, diamine) such as ethylene diamine, hexamethylene diamine,amino acids, such as lysine (where two amine groups react leaving anunreacted carboxylic acid group and oligopeptides (such term includingcompounds containing from one to 100 peptide units) with two reactiveamino groups, among numerous others. Examples of difunctional carboxylicacid-containing compounds include, for example, succinic acid, sebacicacid, among numerous others, including adipic acid, succinic acid,maleic acid, or fumaric acid, maleic acid, COOH-terminatedpolycaprolactone, COOH-terminated polyesters or oligoesters such asCOOH-terminated poly(ethylene succinate) or poly(hexamethylene adipate).Additional examples of such compounds include, for example, C═Ccontaining groups such as fumaric acid (trans) and maleic acid (cis),among others which react with the diisocyanates via their COOH groupswhich leave unreacted double bonds available for further derivation bydifferent mechanisms. Indeed, a large number of molecules are able tostart the polymerization step including polyaminoacids, saccharides,etc. One example may be a polymer where lactide dimer (LD) is notstarted by a PEG chain, but rather by butane diol. A pentamer will beformed with HDI and chain-extended using, for example, PEG 6000.Alternatively, one can generate the HDI-PEG6000-HDI macrodiisocyanateand react such a molecule with, for example, (LA)-BD-(LA)4 triblock toproduce the material -(HDI)-(LA)-BD-(LA)4-HDI-PEG6000-. A huge number ofalternative embodiments are contemplated by the present invention.

When such compounds are used to make AB diblocks, the difunctional diol,diamine or dicarboxylic acid compounds may be terminated with anunreactive or blocking group at one end of the compound, or,alternatively, the compound may simply be end-capped with an unreactivegroup such as an alkyl, cycloalkyl, aryl, aralkyl or related group. Insuch a case, the unreacted or blocked group may be “deblocked” thusproducing an AB diblock which has reactive groups at the terminal end ofthe A block and at the terminal end of the B block. Alternatively, wherethe B block is simply end-capped with an unreactive group, the resultingAB diblock will have but one functional group at the terminal end of theA block, which can be chain-extended, coupled or crosslinked tomulti-diblocks according to the present invention.

The B block may vary in size from about 100 Da (dalton units) up toabout 200,000 Da or higher, with a preferred range of about 1,000 Da upto about 20,000 Da. Most preferably, the B block is a poly(ethyleneoxide) ranging in size from about 3,000 to about 10,000 Da. It isunexpectedly found that the poly(ethyleneoxide) B block provides thegreatest inhibition or reduction in adhesion in the present invention.

The ABA triblock or AB diblock is preferably end-capped withnucleophilic moieties such as hydroxyl or amine groups. Alternatively,these triblocks and diblocks may be end-capped with carboxylate groupsas well. With the preferred nucleophilic end-capping groups in place,the ABA triblock or AB diblock may be readily chain extended usingdifunctional electrophilic compounds such as diisocyanate ordicarboxylic acid compounds (or derivatives of dicarboxylic acids suchas esters or diacyl halides). More preferably, the triblocks or diblocksare end-capped with hydroxyl groups and chain extended with diisocyanatecompounds in order to produce the preferred polymers according to thepresent invention.

The present invention therefore, relates to a method of substantiallyreducing or preventing tissue adhesions in patients comprising exposingdamaged tissue in a patient to a polymeric composition in a structuresuch as a film, gel, dispersion, liquid polymer, spray or viscoussolution form comprising a multiblock polymer according to the presentinvention. Structures such as films which incorporate the polymersaccording to the present invention are preferably characterized by theirfavorable flexibility, mechanical strength and suture-holding ability aswell as being substantially non-water soluble, chain extended, integraland biodegradable. Other structures used in the present invention, aswell as gels, viscous solutions and emulsions, incertain aspects, may bepreferably water soluble. In all aspects according to the presentinvention, certain embodiments may be substantially non-water soluble orwater soluble, depending upon a variety of factors which may beinfluenced by treatment and/or delivery of the present compositions to asite of activity.

Preferably, the molecular weight of triblocks, diblocks and polymersused in the present invention are relatively homogeneous which providesfor advantageous characteristics in films and related structures, gels,dispersions, sprays, liquid polymers and solutions/emulsions.

Preferred polymers used in the present invention as films and otherpreformed structures which make use of ABA triblocks, in contrast to ABdiblocks, are poly(α-hydroxy-carboxylic acid)/poly(oxyalkylene) polymersof the chemical structure:

where a, b and m are positive integers, R is an ethylene and/orpropylene group with the proviso that R is not exclusively a propylenegroup when R′ contains an absence of poly(ethylene oxide), R′ is a C₂ toC₁₂, preferably a C₂ to C₈ alkylene group, a cycloalkyl orcycloalkyl-containing group, an aryl or aryl-containing group,4,4′-diphenylmethane, toluene, naphthalene, 4,4′-dicyclohexylmethane,cyclohexyl, 3,3′-dimethylphenyl, 3,3′-dimethyl-diphenylmethane,4,6′-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene,p-phenylene or a poly(ethylene oxide) containing or poly(ethylene oxide)rich chain and R is H or CH₃. More preferably, R′ is a hexamethylenegroup (C₆ alkylene group), R-is an ethylene group and R₁ is CH₃. Inpreferred embodiments, the integers a and b are equal. In thesepreferred polymers, triblocks, rather than diblocks, are used.

Additional preferred polymers for use in the present invention as filmsand other preformed structures which make use of ABA triblocks, incontrast to AB diblocks, include those of the following structure:

where x, y and m are positive integers, R is an ethylene and/orpropylene group with the proviso that R is not exclusively a propylenegroup when R″ contains an absence of poly(ethylene oxide), R₁ is ahydrogen or methyl group, R″ is a C₀ to C₁₂, preferably a C₂ to C_(8,)alkylene group or a hydroxyl or carboxylic acid substituted alkylenegroup, alkene, a cycloalkyl, hydroxyl or carboxylic acid containingcycloalkyl or cycloalkyl-containing group, an aryl or aryl-containinggroup or a polyoxyalkylene chain comprised of poly(ethylene oxide),poly(ethylene oxide)-co-poly(propylene oxide) or other poly(ethyleneoxide) rich chains. More preferably, R″ is a C₂ to C₄ alkylene group, Ris an ethylene group and R₁ is CH₃. The integers x and y are preferablyequal.

The moiety

may be derived from numerous di- and tricarboxylic acids including, forexample, citric acid, malic acid and tartaric acid, among numerousothers such as oxalic acid, malonic acid, succinic acid,2,3-dimethylsuccinic acid, glutaric acid, 3,3-dimethylglutaric acid,3,3-dimethylglutaric acid, 3-methyladipic acid, adipic acid, pimelicacid, suberic acid, azelaic acid, sebacic acid, 1,9-nonanedicarboxylicacid, 1,10-decanedicarboxylic acid, 1,11-undecanedicarboxylic acid,1,12-dodecanedicarboxylic acid, maleic acid, fumaric acid, diglycolicacid, hydromuconic acid, among others, including equivalents of theseacids. These di- and tricarboxylic acids may be used to chain extend theABA triblocks under controlled conditions so that crosslinking issubstantially prevented. Alternatively, the use of the tricarboxylicacids may result in substantial crosslinking in certain aspects of thepresent invention. In the case of using dicarboxylic acids containingadditional carboxylic acid groups and/or other polar groups such ashydroxyl groups, as in the case of citric acid or malic acid, amongothers, these will tend to enhance the water solubility of the finalpolymeric compositions.

Other embodiments according to the present invention relate to polymericcompositions which have the following general structure:

where j, k and m are positive integers, R is an ethylene and/orpropylene group with the proviso that R is not exclusively a propylenegroup when R′ and R′″ contain an absence of poly(ethylene oxide), R′ isa C₂ to C₁₂, preferably a C₂ to C₈ alkylene group, a cycloalkyl orcycloalkyl-containing group, an aryl or aryl-containing group,4,4′-diphenylmethane, toluene, naphthalene, 4,4′-dicyclohexylmethane,cyclohexyl, 3,3′-dimethylphenyl, 3,3′-dimethyl-diphenylmethane,4,6′-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene,p-phenylene or a poly(ethylene oxide) containing or poly(ethylene oxide)rich chain, R′″ is a polyoxyalkylene chain comprised of poly(ethyleneoxide), poly(ethylene oxide)-co-poly(propylene oxide) or otherpoly(ethylene oxide) rich chains or a diol, diamine or dicarboxylic acid(an OH, NH₂, or COOH terminated molecule reactive with an isocyanate, incertain embodiments, preferably having at least one C═C containingmolecule) or an ABA triblock wherein A is a polyester unit and B is adiol, diamine, dicarboxylic acid or a poly(oxyalkylene) containing orpoly(oxyalkylene) rich chain and R₁ is H or CH₃. Examples of suchcompounds include, for example, OH-terminated diol molecules such asethylene glycol, butanediol, OH-terminated polycaprolactone chainsranging in molecular weight from several hundred up to several thousandor more (4,000+), poly(propylene glycol) also ranging in molecularweight from several hundred to several thousand or more (4000+),OH-terminated polyesters or oligoesters such as OH-terminatedpoly(ethylene succinate) or poly(hexamethyleneadipate) or polyfunctionaldiols such as citric acid or tartaric acid (the latter containing two OHgroups which are reactive with isocyanates and two carboxylic acidgroups, which, in carboxylate form, will function to enhance the overallhydrophilicity of the composition and can serve to provide a materialwith pH dependent water solubility). Additional examples of suchcompounds include amine-containing compounds (preferably, diamine) suchas ethylene diamine, hexamethylene diamine, amino acids, such aslysine(where two amine groups react leaving an unreacted carboxylic acidgroup and oligopeptides with two reactive amino groups, among numerousothers. Examples of difunctional carboxylic acid-containing compoundsinclude, for example, oxalic acid, succinic acid, malic acid, adipicacid, sebacic acid, or fumaric acid, maleic acid, COOH-terminatedpolycaprolactone, COOH-terminated polyesters or oligoesters such asCOOH-terminated poly(ethylene succinate) or poly(hexamethylene adipate).Additional examples of such compounds include, for example, C═Ccontaining groups such as fumaric acid (trans) and maleic acid (cis)which react with the diisocyanates via their COOH groups, leaving theunreacted double bond available for further derivation by differentmechanisms. More preferably, R′ is a hexamethylene group (C₆ alkylenegroup), R is an ethylene group, R′″ is poly(ethylene oxide) and R₁ isCH₃. The integers j and k are preferably equal.

The present invention also relates to compositions for use in reducingor preventing adhesions in a patient comprising a polymer of thechemical structure:

where m and a are positive integers,

-   R is an ethylene group and/or propylene group with the proviso that    R is not exclusively a propylene group, R₁ is H or CH₃ and M is a    non-reactive group, preferably a group selected from a C₁ to C₁₂    alkyl group, an aryl group, an aralkyl group or a substituted C₁ to    C₁₂ alkyl group, aryl group, aralkyl group or a blocking group.    Preferably, R₁ is CH₃.

The present invention also relates to a composition for use in reducingor preventing adhesions in a patient comprising a polymer of thechemical structure:

where m and x are positive integers,

-   R is an ethylene group and/or propylene group with the proviso that    R is not exclusively a propylene group when R″ contains an absence    of poly(ethylene oxide), M is a non-reactive group, R″ is a C₀ to    C₁₂ alkylene group or a hydroxyl or carboxylic acid substituted    alkyl group, a cycloalkyl, a hydroxyl-containing cycloalkyl, or    cycloalkyl-containing group, an aryl or aryl-containing group, or a    polyoxyalkylene chain-containing group comprised of poly(ethylene    oxide), poly(ethylene oxide)-co-poly(propylene oxide) or a    poly(ethylene oxide) rich chain, R₁ is H or CH₃ and M is a    non-reactive group. Preferably, the non-reactive group is a C₁ to    C₁₂ alkyl group, an aryl group, an aralkyl group or a substituted C₁    to C₁₂ alkyl group, an aryl group, an aralkyl group or a blocking    group and more preferably, M is methyl or ethyl.

The present invention also relates to a composition for use in reducingor preventing adhesions in a patient comprising a polymer of thechemical structure:

where m and a are positive integers,

-   R is an ethylene group and/or propylene group with the proviso that    R is not exclusively a propylene group when R′ contains an absence    of poly(ethylene oxide), M is a non-reactive group, R′ is a C₂ to    C₁₂ alkylene group, a cycloalkyl or cycloalkyl-containing group, an    aryl or aryl-containing group, 4,4′-diphenylmethane, toluene,    naphthalene, 4,4′-dicyclohexylmethane, cyclohexyl,    3,3′-dimethylphenyl, 3,3′-dimethyl-diphenylmethane, 4,6′-xylylene,    3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene or    p-phenylene or a poly(ethylene oxide) containing or poly(ethylene    oxide) rich chain and R₁ is H or CH₃. Preferably, the non-reactive    group is a C₁ to C₁₂ alkyl group, an aryl group, an aralkyl group or    a substituted C₁ to C₁₂ alkyl group, an aryl group, an aralkyl group    or a blocking group and more preferably, M is methyl or ethyl.

The present invention also relates to a composition for use in reducingor preventing adhesions in a patient comprising a polymer of thechemical structure:

where m and k are positive integers,

-   R is an ethylene or propylene group with the proviso that R is not    exclusively a propylene group when R′ and R′″ contain an absence of    poly(ethylene oxide), R′ is a C₂ to C₁₂ alkylene group, a cycloalkyl    or cycloalkyl-containing group, an aryl or aryl-containing group,    4,4′-diphenylmethane, toluene, naphthalene,    4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,    3,3′-dimethyl-diphenylmethane, 4,6′-xylylene,    3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene, p-phenylene    or a poly(ethylene oxide) containing or poly(ethylene oxide) rich    chain, R′″ is selected from the group consisting of poly(ethylene    oxide), poly(ethylene oxide)-co-poly(propylene oxide), a    poly(ethylene oxide)-rich chain, a diol, a diamine, a dicarboxylic    acid and an ABA triblock, said diol preferably being selected from    the group consisting of ethylene glycol, butanediol, OH-terminated    polycaprolactone, poly(propylene glycol), OH-terminated polyester or    oligoesters, tartaric acid, said diamine being preferably selected    from the group consisting of ethylene diamine, hexamethylene    diamine, amino acids, and oligopeptides and said dicarboxylic    preferably being selected from the group consisting of succinic    acid, sebacic acid, adipic acid, malic acid, oxalic acid, maleic    acid, fumaric acid, COOH-terminated polycaprolactone, and    COOH-terminated polyesters or oligoesters, wherein A is a polyester    unit and B is selected from the group consisting of poly(ethylene    oxide), poly(ethylene oxide)-co-poly(propylene oxde), a    poly(ethylene oxide) rich chain, a diol, a diamine and a    dicarboxylic acid, R₁ is H or CH₃ and M is a non-reactive group.    Preferably the non-reactive group is a C₁ to C₁₂ alkyl group, an    aryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group,    an aryl group, an aralkyl group or a blocking group and M is methyl    or ethyl.

The present invention also relates to a composition for use in reducingor preventing adhesions in a patient comprising a polymer of thechemical structure:

where m and k are positive integers,

-   R is an ethylene or propylene group with the proviso that R is not    exclusively propylene when R′ contains an absence of poly(ethylene    oxide), R′ is a C₂ to C₁₂ alkylene group, a cycloalkyl or    cycloalkyl-containing group, an aryl or aryl-containing group,    4,4′-diphenylmethane, toluene, naphthalene,    4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,    3,3′-dimethyl-diphenylmethane, 4,6′-xylylene,    3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene, p-phenylene    or a poly(ethylene oxide) containing or poly(ethylene oxide) rich    chain and K is any group derived from a compound which is unable to    initiate ring opening polymerization of a starting lactone.    Preferably, K is a C₁ to C₁₂ alkyl group, an aryl group, an aralkyl    group or a substituted C₁ to C₁₂ alkyl group, an aryl group, an    aralkyl group, or a C═C containing group. Most preferably, K is    methyl or ethyl.

The present invention also relates to a composition for use in reducingor preventing adhesions in a patient comprising a polymer of thechemical structure:

where m and x are positive integers,

-   R is an ethylene and/or propylene group with the proviso that R is    not exclusively a propylene group when R″ and R′″ contain an absence    of poly(ethylene oxide), R₁ is a hydrogen or methyl group, R″ is a    C₀ to C₁₂ alkylene group or a hydroxyl or carboxylic acid    substituted alkyl group, a cycloalkyl, a hydroxyl-containing    cycloalkyl, or cycloalkyl-containing group, an aryl or    aryl-containing group, or a polyoxyalkylene chain-containing group    comprised of poly(ethylene oxide), poly(ethylene    oxide)-co-poly(propylene oxide) or a poly(ethylene oxide) rich    chain, R′″ is selected from the group consisting of poly(ethylene    oxide), poly(ethylene oxide)-co-poly(propylene oxide), a    poly(ethylene oxide)-rich chain, a diol, a diamine, a dicarboxylic    acid and an ABA triblock, said diol preferably being selected from    the group consisting of ethylene glycol, butanediol, OH-terminated    polycaprolactone, poly(propylene glycol), OH-terminated polyester or    oligoesters and tartaric acid, said diamine being preferably    selected from the group consisting of ethylene diamine,    hexamethylene diamine, amino acids, and oligopeptides and said    dicarboxylic preferably being selected from the group consisting of    succinic acid, sebacic acid, adipic acid, malic acid, oxalic acid,    maleic acid, fumaric acid, COOH-terminated polycaprolactone, and    COOH-terminated polyesters or oligoesters, wherein A is a polyester    unit and B is selected from the group consisting of poly(ethylene    oxide), poly(ethylene oxide)-co-poly(propylene oxde), a    poly(ethylene oxide) rich chain, a diol, a diamine and a    dicarboxylic acid, R₁ is H or CH₃ and M is a non-reactive group.    Preferably, the non-reactive group is a C₁ to C₁₂ alkyl group, an    aryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group,    an aryl group, an aralkyl group or a blocking group and M is methyl    or ethyl.

Other embodiments of the present invention are directed to a compositionfor use in reducing or preventing adhesions in a patient comprising apolymer of the chemical structure:

where m and a are positive integers,

-   R is an ethylene group and/or propylene group with the proviso that    R is not exclusively a propylene group when R′ contains an absence    of poly(ethylene oxide), M is a non-reactive group, R′ is a C₂ to    C₁₂ alkylene group, a cycloalkyl or cycloalkyl-containing group, an    aryl or aryl-containing group, 4,4′-diphenylmethane, toluene,    naphthalene, 4,4′-dicyclohexylmethane, cyclohexyl,    3,3′-dimethylphenyl, 3,3′-dimethyl-diphenylmethane, 4,6′-xylylene,    3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene,    p-phenylene, or a poly(ethylene oxide) containing or    poly(ethyleneoxide) rich chain, M is a non-reactive group, R₁ is H    or CH₃. Preferably, the non-reactive group is a C₁ to C₁₂ alkyl    group, an aryl group, an aralkyl group or a substituted C₁ to C₁₂    alkyl group, an aryl group, an aralkyl group or a blocking group and    M is methyl or ethyl.

In various materials according to the present invention which areincluded in preformed and non-preformed materials such as films, viscoussolutions, suspensions and gels, among others, the polymers may compriseABA triblocks or AB diblocks as disclosed hereinabove, which may bechain extended, coupled and/or crosslinked using a highly watersoluble/water dispersible chain extender or crosslinking agent. Althoughin many preferred embodiments the B block of the ABA triblock or ABdiblock is hydrophilic and will have a high degree of compatibility withwater, thus allowing certain of the polymeric films according to thepresent invention to absorb large quantities of water or dissolve inwater, it is the hydrophilic chain extender or coupler used in variouspolymers according to the present invention which utilize hydrophobicand hydrophilic B blocks, which allows delivery of these polymercompositions in aqueous solutions. Although in the present invention theABA triblocks and AB diblocks are preferably non-water soluble(especially, for example, in the case of films and in other aspects ofthe present invention), in a number of aspects of the present inventionincluding films, or other preformed structures, and in viscoussolutions, gels, dispersions and sprays, the use of ABA triblocks and ABdiblocks which are substantially water soluble may be advantageous. Oneof ordinary skill will readily know how to modify the polymers accordingto the present teachings in an effort to adjust the formulations tomaximize delivery within a particular treatment context.

In the present application, the following chain extenders or couplingagents find use in preparing pre-polymerized, non-preformed polymerssuch as gels and viscous solutions having desirable characteristics forreducing or preventing post-operative adhesion:

where R′ is a C₂ to C₁₂, preferably a C₂ to C₁ alkylene group, acycloalkyl or cycloalkyl-containing group, an aryl or aryl-containinggroup, 4,4′-diphenylmethane, toluene, naphthalene,4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene or p-phenylene. Equivalents ofdiisocyanates may also be used as chain extenders in the presentinvention. Preferred chain extenders may include water solublemacrodiisocyanates including isocyanate terminated poly(oxyalkylene)diisocyanates or isocyanate-terminated polymers comprising poly(ethyleneoxide), polyethylene oxide)-co-poly(propylene oxide) and poly(ethyleneoxide) containing and poly(ethylene oxide) rich schains, which may bewater-soluble or non-water soluble, among others.

Additional preferred chain extenders for use in the present inventioninclude, example those according to the formula:

where R″ is a C₀ to C₁₂, preferably a C₂ to C_(8,) alkylene group or ahydroxyl or carboxylic acid substituted alkylene group, alkene, acycloalkyl, hydroxyl or carboxylic acid containing cycloalkyl orcycloalkyl-containing group, an aryl or aryl-containing group or apoly(oxyalkylene) chain comprised of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide) or other poly(ethylene oxide) containingor poly(ethylene oxide) rich chains [i.e., where poly(ethylene oxide) isincluded in an amount ranging from at least about 50% by weight of thepolymeric chain and] L is hydroxyl, a halide such as Cl, I or Br or anester group which can be prepared from a hydroxyl group such as analkyl, phenyl, benzyl or substituted alkyl, phenyl or benzyl group,include activated ester groups such as a tosyl group, mesyl group orrelated activated groups. It is noted that diacids according to thisaspect of the present invention may also find use as B blocks in certainABA triblocks and AB diblocks according to the present invention.

It is noted that in choosing ABA triblocks or AB diblocks forformulating viscous solutions and gels according to the presentinvention, care must be given to providing a good balance ofstrength/structural integrity and biodegradability from the A block,hydrophilicity/anti-adhesion activity from the B block and furtherhydrophilicity in the form of water solubility/water dispersibility fromthe chain extender, coupling agent and/or crosslinking agent, where suchagent is used. Notwithstanding certain of the embodiments previouslydiscussed, in the present invention, non-water soluble triblocks ordiblocks such as are utilized in film applications according to thepresent invention also may be advantageously employed in viscoussolution/gel applications.

The above-described chemical formulas provide insight into the chainextended and crosslinked polymers which are used in the presentinvention. In the case of polymers which are preferably used innon-preformed polymers such as gels, dispersions, sprays and/or viscoussolutions according to the present invention, the ultimate polymericcomposition is preferably water soluble/dispersible and the polymers arepreferably chain extended or crosslinked utilizing hydrophilic chainextenders or crosslinking agents, for example, diisocyanate terminatedpoly(alkylene glycol) chains comprising a central polyalkylene glycolchain such as poly(ethylene oxide), capped by two diisocyanatecompounds, among numerous others. Examples include the use ofpoly(ethylene glycol) chains with a molecular range between 200 and20,000, hexamethylene diisocyanate or a related diisocyanate aspreviously described being the diisocyanate. By employing non-watersoluble or water soluble ABA triblocks or AB diblocks and preferablyemploying water soluble/dispersible chain extenders and/or crosslinkingagents, polymer compositions which are used in viscous solution and gelapplications provide favorable strength and structural integrity,biodegradability (the rate of which may be influenced by the length andhydrophobicity of the A block and the overall hydrophilicity of thepolymer), flexibility and anti-adhesion activity from the PEG segmentsin the polymer and water solubility/dispersibility from the selectivechain extenders which are used.

In addition to being useful for substantially reducing or preventingadhesions, the present polymers may also be used to deliver bioactivecompositions to a site of activity within the patient's body. Thisaspect of the present invention is secondary to the anti-adhesioncharacteristics of the inventive polymers. It is particularlyadvantageous that the present polymers may be used to deliver bioactiveagents which may serve to enhance the healing of the wounds created by asurgical procedure, a disease state or other condition associated withthe tissue to be treated.

Exemplary bioactive agents which may be delivered pursuant to themethods according to the present invention include, for example,anticoagulants, for example heparin and chondroitin sulphate,fibrinolytics such as tPA, plasmin, streptokinase, urokinase andelastase, steroidal and non-steroidal anti-inflammatory agents such ashydrocortisone, dexamethasone, prednisolone, methylprednisolone,promethazine, aspirin, ibuprofen, indomethacin, ketoralac,meclofenamate, tolmetin, calcium channel blockers such as diltiazem,nifedipine, verapamil, antioxidants such as ascorbic acid, carotenes andalpha-tocopherol, allopurinol, trimetazidine, antibiotics, especiallynoxythiolin and other antibiotics to prevent infection, prokineticagents to promote bowel motility, agents to prevent collagencrosslinking such as cis-hydroxyproline and D-penicillamine, and agentswhich prevent mast cell degranulation such as disodium chromolglycate,among numerous others.

In addition to the above agents, which generally exhibit favorablepharmacological activity related to promoting wound healing, reducinginfection or otherwise reducing the likelihood that an adhesion willoccur, other bioactive agents may be delivered by the polymers of thepresent invention include, for example, amino acids, peptides, proteins,including enzymes, carbohydrates, antibiotics (treat a specificmicrobial infection), anti-cancer agents, neurotransmitters, hormones,immunological agents including antibodies, nucleic acids includingantisense agents, fertility drugs, psychoactive drugs and localanesthetics, among numerous additional agents.

The delivery of these agents will depend upon the pharmacologicalactivity of the agent, the site of activity within the body and thephysicochemical characteristics of the agent to be delivered, thetherapeutic index of the agent, among other factors. One of ordinaryskill in the art will be able to readily adjust the physicochemicalcharacteristics of the present polymers and thehydrophobicity/hydrophilicity of the agent to be delivered in order toproduce the intended effect. In this aspect of the invention, bioactiveagents are administered in concentrations or amounts which are effectiveto produce an intended result. It is noted that the chemistry ofpolymeric composition according to the present invention can be modifiedto accommodate a broad range of hydrophilic and hydrophobic bioactiveagents and their delivery to sites in the patient.

Synthesis of Polymers According to the Present Invention

In general, the synthesis of the present polymers proceeds by firstsynthesizing an ABA triblock or AB diblock. In this general reaction, apre-prepared poly(oxyalkylene) B block (which can be purchased orsynthesized from an initiating diol and an excess of an appropriateepoxide depending upon the length of the block desired) is preferablyreacted with a hydroxyacid or its cyclic dimer to produce the lowmolecular weight ABA triblock or AB diblock. Essentially, thepoly(oxyalkylene) block which is generally endcapped with hydroxylgroups or, in the case of an AB diblock is capped at one end with ahydroxyl group and at the other end with a non-reactive group, reactswith the hydroxyacid or its cyclic dimer to produce an ABA triblock orAB diblock which is end-capped with a hydroxyl group or other group(s).

Once the ABA triblock or AB diblock is formed, the hydroxyl groups atthe end(s) of the molecule are reacted with difunctional chain extendersor couplers, for example, diisocyanates. This reaction produces a chainextended polymer which is readily used to prepare films and variousrelated structures, gels, dispersions, suspensions, and viscoussolutions of the present invention. In the case of certain polymers,these are of sufficiently low molecular weight so that they are inliquid form without the need to add additional solvent.

Generally, during the first stage of the reaction in which the lowmolecular weight ABA triblock or AB diblock is formed, the overallmolecular weight and the length of the different segments will bedetermined by the molecular weight of the poly(oxyalkylene) block chosento initiate the reaction, by the number of moles of hydroxyacid, itscyclic dimer or related compounds, which is reacted with thepoly(oxyalkylene) block and the catalyst and various experimentalparameters such as the heat and the reaction time. Thereafter, the ABAtriblock or AB diblock is chain extended, coupled and/or crosslinked toproduce polymers containing ABA triblocks or AB diblocks.

A preferred synthesis of the present polymers involves the use of thecyclic ester or lactone of lactic acid and glycolic acid. The use oflactide or glycolide as the reactant will enhance the production of ABAtriblocks or AB diblocks which have relatively narrow molecular weightdistributions and low polydispersity.

In this preferred method, lactide or glycolide (the cyclic dimer oflactic acid or glycolic acid, respectively), rather than lactic acid orglycolic acid, is first used to synthesize the ABA triblock or ABdiblock from the starting poly(oxyalkylene) block. Once the triblock ordiblock is obtained, the hydroxyl end-capped triblock or diblock isreacted with a diisocyanate, preferably hexamethylene diisocyanate.

The synthesis of the ABA triblock or Ab diblock preferably proceeds byway of a ring-opening mechanism, whereby the ring opening of the lactideor glycolide is initiated by the hydroxyl end groups of the PEG chainunder the influence of a tin catalyst (stannous octoate). An ABA typetriblock or AB type diblock is generated at this point, the molecularweight of which is a function of both the molecular weight of thecentral PEG chain and the length of the PLA lateral block(s). Typically,the molecular weight of the triblock spans between about 4,000 to about30,000 (but may be as low as 1,000 or less and as high as 250,000 ormore). In the case if the diblock, the molecular weight may range as lowas several hundred to upwards of 50,000 or more. After synthesis of theABA triblock or ABA diblock, the final polymer is preferably obtained bychain extending the hydroxyl terminated triblocks with difunctionalreactants such as isocyanates, most preferably hexamethylenediisocyanate.

The chemical and physical properties of the different polymers will varyas a function of different parameters, the molecular weight of the PEGand PLA segments along the backbone being of particular importance.

The preferred method has several advantageous characteristics including:

-   -   1. a rapid, nearly quantitative reaction which is complete in        from 1 to 3 hours;    -   2. the reaction takes place under moderate reaction conditions        (140° C.) thus minimizing side reactions,    -   3. the resulting triblock or diblock contains an extremely        narrow polydispersity (P=1.3-1.4 or better; and    -   4. the triblock or diblock contains little or no homopolymer.        Preparation of Adhesion Barrier Structures Barrier structures        (which term includes films as well as cylinders and related        three-dimensional structures) for use in the present invention        are prepared by first producing the polymer according to the        present invention and then dissolving the polymer in a solvent,        such as chloroform, methylene chloride or a related organic        solvent. Films, for example, are preferably prepared by placing        the solution containing polymer in a mold or a related        receptable and then allowing the solvent to evaporate. The        resulting film is homogeneous and of uniform thickness and        density. The film may be used as prepared or cut into segments        for application to a desired site in a patient. In addition to        the above-described solvent cast method, a continuous solvent        cast process, a thermal cast method or related methods well        known in the art may be used to make films and other structures        according to the present invention.

In order to prepare other three dimensional structures of polymer, suchas cylinders and related shapes, these may be cast or molded usingvarious techniques, starting with solid polymer. Methods to producethese structures using these techniques are well known in the art.

Preparation of Gels, Viscous Solutions and Dispersions

In order to prepare the gels, viscous solutions and dispersionsaccording to the present invention, polymer in powder, flakes or otherrelated form is dissolved or suspended in an aqueous solution,preferably sterile isotonic saline solution, generally at roomtemperature and then mixed in the solution to produce the final gel,viscous solution or dispersion. Viscosity of the system is readilyadjusted by adding further polymer or aqueous solution. The gels,viscous solutions and dispersions are utilized under sterile conditions.

While not being limited by way of theory, it is believed that the chainextended polymers of the present invention form integral layers infilms, gels or viscous solutions when applied to tissue for surgicalapplications. The resulting integral polymers provide an excellentbarrier which substantially reduces the formation of post-operativeadhesions.

Having generally described the invention, reference is now made to thefollowing examples intended to illustrate preferred embodiments andcomparisons but which are not to be construed as limiting to the scopeof this invention as more broadly set forth above and in the appendedclaims.

EXAMPLES Example 1 Effect of Polymer Films on Adhesion

The purpose of this experiment was to test the efficacy of EO/LA films(ratios 2.5, 3.3. and 4.0) on the formation of adhesions in a rabbitmodel of adhesion formation between the sidewall and the bowel.

Materials and Methods

Animals

Twenty female New Zealand rabbits, 2.4-2.7 kg, were purchased andquarantined for at least 2 days prior to use. The rabbits were housed ona 12:12 light: dark cycle with food and water available ad libitum.

Synthesis of Materials

The synthesis of the polymers can be summarized as follows:

1. ABA triblock was synthesized as follows:

Polyethylene glycol (MW=6,000) was dried in vacuo overnight at 80° C.Thereafter, the PEG was cooled down to room temperature, the vacuum wasbroken by flushing dry N₂ through the system and lactide is thereafteradded in an appropriate amount (depending upon the length of the A blockdesired). The mixture of PEG and lactide is placed in an oil bath at140° C. and after 2-3 minutes (which is generally required to homogenizethe system), stannous octoate is added (the catalyst/lactide mole ratiois 1/400). The mixture is then flushed with N₂ for a period of about 5minutes, whereupon the N₂ is removed and the flask containing PEG andlactide is then capped and stirred at 140° C. in an oil bath for 2hours. At the end of a 2 hour period, the mixture is removed from theoil bath, allowed to cool, dissolved in chloroform and precipitated inether. The precipitate is thereafter collected and dried overnight invacuo at 50° C. It is then solubilized in chloroform and the chloroformis evaporated to form a film of approximately 10 mil thickness.

2. The Polymer was synthesized as follows:

The synthesis of the polymers is completed by chain extending the ABAtriblocks by reacting their hydroxyl-terminated groups withdiisocyanates, typically hexamethylene diisocyanate (HDI). The triblockobtained above is dried at 80° C. in vacuo for a period of two hours.After the two hour period, vacuum is broken by flushing N₂ through thesystem and a minimal amount of dry dioxane to dissolve the triblock isadded. The required amount of catalyst is dissolved in dioxane (about 5ml) and added to the triblock. 15 ml of dry dioxane is introduced into aseparatory funnel and the required amount of HDI is added (theHDI:catalyst molar ratio is 5:1, and the HDI is in a 7% molar excessrespective to the triblock- the typical Triblock:HDI:Catalyst molarratios are, therefore, 1.0:1.07:0.2, respectively). Once the triblock isfully dissolved, the HDI solution is added dropwise (over a period of 30minutes) to the triblock solution. A condenser is then connected to thereaction flask to prevent dioxane loss and the reaction is continued fora period of 2.5 hours. After 2.5 hours, the reaction is removed from theoil bath, allowed to cool and the polymer solution is precipitated withether. The precipitated polymer is then collected and dried overnight at50° C. The material is then solubilized in chloroform and the chloroformis evaporated (room temperature overnight followed by 5 hours undervacuum at 40° C.) to form a film of approximately 10 mil thickness.

The final polymers used in this experiment had EO/LA ratios of 2.5, 3.3and 4.0.

-   Materials: The above-obtained films were used in the following    experiments. The sutures used were as follows: 6-0 Prolene (Ethicon,    Raritan, N.J.) was used to tack the film in place and 3-0 coated    Dexon II suture (Davis and Geck, Manati, PR) was used to close the    peritoneum and skin.-   Sidewall Model: Rabbits were anesthetized with a mixture of 55 mg/kg    ketamine hydrochloride and 5 mg/kg Rompun intramuscularly. Following    preparation for sterile surgery, a midline laparotomy was performed.    The cecum and bowel were exteriorized and digital pressure was    exerted to create subserosal hemorrhages over all surfaces. The    damaged intestine was then lightly abraded with 4″ 4×4 ply sterile    gauze until punctate bleeding was observed. The cecum and bowel was    then returned to its normal anatomic position. A 3×3 cm² area of    peritoneum and transversus abdomninous muscle was removed on the    right lateral abdominal wall. The prepared film (see below) was    sutured in place using 6-0 prolene at 6 sites (at each corner and in    the center of the side of the film on two sides). After 31-32 days,    the rabbits were terminated and the percentage of the area of the    sidewall injury that was involved in adhesions was determined. In    addition, the tenacity of the adhesions was scored using the    following system:    -   0=No adhesions    -   1=mild, easily dissectable adhesions    -   2=moderate adhesions, non-dissectable, does not tear the organ    -   3=dense adhesions, non-dissectable, tears organ when removed        A reduction in either the area or the tenacity of the adhesions        was considered to be beneficial.-   Preparation of Film: The films were stored at room temperature in a    desiccator until the day of surgery. On the day of surgery, the film    was cut to 3 cm×3 cm in sterile conditions. Ten to 12 minutes prior    to placement, the film was placed in sterile, double distilled water    to allow hydration. During hydration, the films went from opaque to    clear and increased in size proportionate to the EO/LA ratio (the    higher the ratio the more the increase). Thereafter, the film was    rinsed with phosphate buffered saline (pH 7.4) to restore    isotonicity to the surface. Just prior to placement, the film was    blotted on sterile gauze to remove excess moisture.-   RESULTS: During the early postoperative interval, two rabbits died.    Coincidentally, both received the film of the 3.3 ratio. Postmortem    necropsy revealed nothing unusual and the deaths were attributed to    the surgical procedure. No inflammation was noted intraperitoneally.

One rabbit from the group that received the film with the ratio 2.5 wassacrificed 13 days later. Some material was present at the site(identity unknown). One rabbit from the group that received the filmwith the ratio 4.0 died 24 days after surgery. No reason for themortality was noted upon necropsy.

One month after surgery, the remaining rabbits were sacrificed and thedegree of adhesion formation determined (Table 1). At surgery, 5 rabbitswere controls. However, at necropsy, 6 rabbits had been given controlnumbers with two rabbits given the same number (1-2 on the surgery day).One number from the group that had film with the ratio 4.0 was missing(2-1 from surgery day). Of the rabbits that were confirmed as controls(4 of the 6), 3 had adhesions (one with 80% and 2 with 100% of the areaof the sidewall injury with adhesions). In all of these rabbits, thetenacity of the adhesions was 3+. All of the rabbits with films placedat surgery had no adhesions at necropsy. Of the two rabbits with thesame number, one had 100% of the sidewall injury area covered with 3+adhesions and the other had no adhesions at the site of injury.

DISCUSSION: The films made from various ratios of EO/LA were highlyefficacious at the reduction of adhesion formation. In the controlrabbits which had surgery and the sutures placed in the same pattern asthat in the treated rabbits, the majority (60%, 75% or 80% dependingupon the inclusion of the mismarked rabbit) of the rabbits had theformation of severe, cohesive adhesions at the site of sidewall injury.In the rabbits that were confirmed to have been given the film, allrabbits had no adhesions at the site of adhesion formation. At two weeksand later, the site of injury appeared fully healed. TABLE 1 Area ofAdhesion Formation at Site of Sidewall Injury % Area Involved Treatment0 1-25 26-50 51-75 76-100 Surgical Control  20* 0 0 0 75 n = 4 EO/LARatio 2.3 100 0 0 0 0 n = 4 EO/LA Ratio 3.3 100 0 0 0 0 n = 3 EO/LARatio 4.0 100 0 0 0 0 n − 3*1 out of 5 animals had no adhesions.

It is to be understood that the examples and embodiments describedhereinabove are for the purposes of providing a description of thepresent invention by way of example and are not to be viewed as limitingthe present invention in any way. Various modifications or changes thatmay be made to that described hereinabove by those of ordinary skill inthe art are also contemplated by the present invention and are to beincluded within the spirit and purview of this application and thefollowing claims.

1-92. (canceled)
 93. A composition for use in reducing or preventingadhesions in a patient comprising a polymer of the chemical structure:

Where m and k are positive integers, R is an ethylene or propylene groupwith the proviso that R is not exclusively ethylene where R′ contains anabsence of poly(ethylene oxide), R′ is a C₂ to C₁₂ alkylene group, acycloalkyl or cycloalkyl-containing group, an aryl or aryl-containinggroup, 4,4′-diphenylmethane, toluene, naphthalene,4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene, p-phanylene or a poly(ethylene oxide)containing or poly(ethylene oxide) rich chain and K is any group derivedfrom a compound which is unable to initiate ring opening polymerizationof a starting lactone, said polymeric composition having an EO/LA ratiowhich falls within the range of about 0.1 to about
 100. 94. Thecomposition according to claim 83 wherein K is a C₁ to C₁₂ alkyl group,an aryl group, an aralkyl group or a substituted C1 to C12 alkyl group,an aryl group, an aralkyl group, a C═C-containing group.
 95. Thecomposition according to claim 83 where K is methyl or ethyl.
 96. Acomposition for use in reducing or preventing adhesions in a patientcomprising a polymer of the chemical structure:

where m and x are positive integers, R is an ethylene or propylene groupwith the proviso that R is not exclusively a propylene group when R″ andR′″ contain an absence of poly(ethylene oxide) , R1 is a hydrogen ormethyl group, R″ is a C₀ to C₁₂ alkylene group or a hydroxyl orcarboxylic acid substituted alkyl group, a cycloalkyl, ahydroxyl-containing cycloalkyl, or cycloalkyl-containing group, an arylor aryl-containing group, or a polyoxyalkylene chain-containing groupcomprised of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide) or a poly(ethylene oxide) rich chain,R′″ is selected from the group consisting of poly(ethylene oxide),poly(ethylene oxide)-co-poly(propylene oxide), a poly(ethyleneoxide)-rich chain, a diol, a diamine, a dicarboxylic acid and an ABAtriblock, wherein A is a polyester unit and B is selected from the groupconsisting of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide) , a poly(ethylene oxide)-rich chain, adiol, a diamine, and a dicarboxylic acid, R₁ is H or CH₃ and M is anon-reactive group, said polymeric composition having an EO/LA ratiowhich falls within the range of about 0.1 to about
 100. 97. The methodaccording to claim 86 wherein said diol is selected from the groupconsisting of ethylene glycol, butanediol, (H-terminatedpolycaprolactone, poly(propylene glycol), (H-terminated polyester oroligoesters, tartaric acid, said diamine is selected from the groupconsisting of ethylene diamine, hexamethylene diamine, amino acids, andoligopeptides and said dicarboxylic acid is delected from the groupconsisting of succinic acid, sebacic acid, adipic acid, malic acid,oxalic acid, maleic acid, fumaric acid, COOH-terminatedpolycaprolactone, and COOH-terminated polyesters or oligoesters.
 98. Thecomposition according to claim 86 wherein said non-reactive group is aC₁ to C₁₂ alkyl group, an aryl group, an aralkyl group or a substitutedC₁ to C₁₂ alkyl group, an aryl group, an aralkyl group or a blockinggroup.
 99. The composition according to claim 86 where M is methyl orethyl.
 100. A composition for use in reducing or preventing adhesions ina patient comprising a polymer of the chemical structure:

where m and a are positive integers, R is an ethylene group and/orpropylene group with the proviso that R is not exclusively a propylenegroup when R′ contains an absence of poly(ethylene oxide), M is anon-reactive group, R′ is a C₂ to C₁₂ alkylene group, a cycloalkyl orcycloalkyl-containing group, an aryl or arly-containing group,4,4′-diphenylmethane, toluene, naphthalene, 4,4′-dicyclohexylmethane,cyclohexyl, 3,3′dimethylphenyl, 3,3′-dimethyl-diphenylmethane,4,6′-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene,p-phenylene or a poly(ethylene oxide) containing or poly(ethylene oxide)rich chain, M is a non-reactive group, R₁ is H or CH₃ said polymericcomposition having an EO/LA ration which falls within the range of about0.1 to about
 100. 101. The composition according to claim 90 whereinsaid non-reactive group is a C₁ to C₁₂ alkyl group, an aryl group, anaralkyl group or a substituted C₁ to C₁₂ alkyl group, an aryl group, anaralkyl group or a blocking group.
 102. The composition according toclaim 91 where M is methyl or ethyl.